The role of the hormone norepinephrine, 4-(2-amino-1-hydroxyethyl)-1,2-benzenediol, and its congeners such as epinephrine or isoproterenol as transmitter substances of the peripheral sympathetic nerve endings and of certain synapses in the central nervous system is well documented. Epinephrine, 4-[1-hydroxy-2-(methyamino)-ethyl]-1,2-benzenediol, which acts as a stimulator of the sympathetic nervous system, thus producing a broad range of physiological effects such as vasopression, increased blood pressure, cardiac stimulation, increased cardiac output, glucose release and glycogenolysis, is also extremely well known and studied. Generically in a chemical sense, such hormones are classified as catecholamines. That is, they possess the characteristic hydroxyl groups substituted at the 3 and 4 positions on a benzene ring and the hydroxy-alkylamine side chain attached to the number 1 carbon of the benzene ring. More specifically norepinephrine has the structure: ##STR1## while epinephrine has the structure: ##STR2##
Although norepinephrine and epinephrine are closely related chemically, their physiological effects are somewhat different with respect to reactions mediated by the hormones, tissue and organs affected, and the strength of their respective activities. Thus, norepinephrine primarily mediates nerve impulses as a transmitter substance of the sympathetic nerve endings. Epinephrine, on the other hand, operates primarily as a vasopressor, heart stimulant, and blood volume and pressure stimulant. The two molecular structures norepinephrine and epinephrine produce qualitatively similar but quantitatively different physiological effects. In some instances these effects are diverse and general, whereas, in others, the effect is very specific. It is therefore of interest to explore the possibility of devising epinephrine and norepinephrine related molecules which will exhibit biological activity in general and perhaps selected activity which will permit "targeting" various physiological functions on a more selective basis than is possible with the naturally occurring hormones.
Unfortunately, the epinephrine and norepinephrine structures, (generically-catecholamines) are particularly sensitive to alteration of the molecular structure insofar as maintenance of physiological activity is concerned. Thus when aromatic substitutions are made at the 2 or 5 carbon positions on the benzene ring, activity may be destroyed. On the other hand, a number of active molecules have been obtained by alkylation of the side chain amine group, e.g., the isopropyl homolog of epinephrine, isoproterenol; which has the structure: ##STR3##
The preparation of other biologically active catecholamines would, of course, be of great interest, especially where such derivatives may exhibit specialized effects on biological systems, or where the derivative could be further conjugated with other "carrier" molecular structures without affecting the basic physiological functions which are characteristic of the catecholamine hormones.